Solubilization of heavy metal salts of 1-hydroxy-2-pyridinethione

ABSTRACT

METHOD FOR SOLUBILIZING HEAVY METAL SALTS OF 1-HYDROXY2-PYRIDINETHIONE BY ADMIXTURE WITH AN AMINE. SOLUTIONS OF SUCH SALTS IN AMINES.

United States Patent Ofice 3,636,213 Patented Jan. 18, 1972 3,636,213 SOLUBILIZATION (3F HEAVY METAL SALTS OF I-HYDROXY-Z-PYRIDINETHIONE Terry Gerstein, Brooklyn, and William Perlberg, Bellnlore, N.Y., and Milton Schwarz, Westport, Conn., assignors to Revlon, Inc., New York, N.Y.

No Drawing. Filed Feb. 19, 1968, Ser. No. 706,604 Claims priority, application Great Britain, Feb. 20, 1967, 8,055/ 67 Int. Cl. A61k 7/06; A61l 23/00 US. Cl. 424-245 6 Claims ABSTRACT OF THE DISCLOSURE Method for solubilizing heavy metal salts of l-hydroxy- 2-pyridinethione by admixture with an amine. Solut1ons of such salts in amines.

The present invention relates to methods of solubilizing heavy metal salts of 1-hydroxy-2-pyridinethione, to such solubilized salts, and to compositions containing the solubilized salts. More in particular, the present invention relates to solubilizing heavy metal salts of l-hydroxy-2- pyridinethione by admixture of the salts with an amine, suitably a primary amine, or with a polyalkylene imine, to such solubilized salts, and to compositions containing the solubilized salts.

Heavy metal salts of 1-hydroxy-2-pyridinethione (hereinafter often referred to as pyridinethione) are described in detail in US. Pat. 2,809,971. As there discussed, the heavy metal salts are conveniently prepared by reaction of a soluble heavy metal compound with a soluble salt of pyridinethione, such as an alkali metal salt or ammonium salt. On combination of these reactants, the heavy metal salt precipitates and is recovered. By heavy metal salts in the present specification are meant salts like those disclosed in said US. Pat. 2,809,971, i.e. salts in which the heavy metal group is, inter alia, copper, iron, manganese, tin, mercuery, cobalt, chromium, lead, gold, cadmium, nickel, silver, zinc, titanium, arsenic, antimony, zirconium, or bismuth. As in the aforementioned patent, the term heavy metal as employed in the present specification includes elements of metallic character such as arsenic, characterized in the patent as semi-metals.

The heavy metal salts of pyridinethione are useful as fungicides and bactericides, and certain of them are particularly adaptable to topical application to the skin. The zinc salt specifically is quite effective as an agent against seborrhea, and has found wide acceptance in the cosmetic art for use in soaps, shampoos, hairdressings, and the like.

One disadvantage of the heavy metal salts of pyridinethione, such as the zinc salt, is their insolubility in common solvents. The zinc salt, for example, is substantially insoluble in water (10-20 p.p.m.), ethanol (310 p.p.m.), benzene (35 p.p.m.), petroleum oils, and most common organic solvents. The material is slightly more soluble in chloroform (3400 ppm), dimethyl formamide (8100 ppm), and dimethyl sulfoxide (5.13 percent). Accordingly, it has been found difiicult to formulate suitable cosmetic and other compositions containing these heavy metal salts in dissolved form. The few solvents known for the salts are unacceptable for cosmetic uses and the salts must always be present in such compositions in dispersed form, necessarily rendering the compositions opaque. Although there are soluble salts of pyridinethione, such as the alkali metal salts, these soluble salts have been found toxic and unacceptable for use in cosmetic or dermatologic compositions for topical application to the skin.

It has been found according to the present invention that the insoluble heavy metal salts of pyridinethione can be solubilized in common organic solvents and/or water by combination with an amine, suitably a primary amine, or with a polyalkylene imine. Solutions of the heavy metal salts in an amine or imine can be used per se for certain specialized cosmetic applications, such as hair straightening. However, most commonly, the resultant alkaline solutions are partially neutralized to form compositions of a pH acceptable for more general application to the skin and hair.

The increased solubility of heavy metal pyridinethione salts in alkaline media has been observed in the art. For example, the zinc salt is soluble in Water at pH 7 to an extent of about 10-20 parts per million. This is raised to a value of 35-50 parts per millon at a pH of 8. According to the present invention, however, the solubility of the zinc salt in compositions having a pH of about 8 can be as high as at least 200 parts per million or higher.

The biological activity of salts such as zinc pyridinethione has been reported to increase in alkaline solutions as a result of its greater solubility. Because of the increased biological efficacy of the salts solubilized according to the present invention, minimum concentrations of the salt can be used in compositions containing the same to produce maximum beneficial elfects. Nevertheless, the increased solubility and increased biological activity of the solubilized heavy metal salts have not been observed to involve increased toxicity of the solubilized materials.

As amines useful for solubilizing heavy metal pyridinethione salts a wide variety of materials, principally primary amines, can be used. Suitable amines include such diverse materials as the alkyl and aryl monoand polyamines including 1,3-propane diamine, dodecyl amine and other fatty amines, aniline, N-methyl aniline, and benzylamine; amino alcohols such as 2-amino-2-methyl-1,3-propanediol, and ethanolamine; and primary amines additionally containing aliphatic hetero atoms of nitrogen, oxygen, or sulfur such as imino-bis-propylamine, methylimino-bispropylamine, N-(3-aminopropyl)-diethanolamine, bis-(2- aminoethyl) sulfide, diglycol amine, di-ethoxyand triethoxy-propylamine, and S-methoxy-n-propylamine. The heavy metal pyridinethioine salts are soluble in these typical materials to an extent of at least about 10 percent. For example, zinc pyridinethione is soluble to more than 10 percent in dodecyl amine, and to about 42 percent in diglycol amine. The last mentioned amine is a preferred amine for solubilizing zinc pyridinethione.

The heavy metal salts are somewhat less soluble, but still usefully so, in amines such as ethoxylatedor propoxylated-polyethylene imine (about one part of alkoxy groups to 9 parts by weight of imine); some heterocyclic secondary amines such as pyrrolidine, piperidine, morpholine and 4-(3-aminopropyl) morpholine; and isocyclic amines such as cyclohexyl amine. Although the salts are also soluble to some extent in ammonia, the high alkalinity of the solutions precludes the use of any but small quantities in most formulations, With a resultant low final concentration of solubilized salt.

To speed solution of the salt in these substances, the salt and amine may be warmed, for example by gentle heating on a steam bath. The resulting solutions can be diluted with organic solvent materials such as ethanol or with small amounts of Water. However, the addition of a large amount of water to combinations of an amine of the above type with a heavy metal pyridinethione salt usually results in undue lowering of the pH and precipitation of a portion of the salt.

Solutions of pyridinethione salts in an amine such as diglycol amine have a pH value of about 11. Such highly alkaline solutions per se have limited utility, for example as hair straightening agents having anti-seborrheic properties. However, the most useful cosmetic and dermatologic compositions have a lower pH, commonly between about 7.5 and 9.5. The alkaline amine solutions of heavy metal salts of pyridinethiones disclosed above can be neutralized to these lower pH values while still retaining relatively large amounts of the salt in soluble form in the resulting solution. Although any acid can be used for the neutralizing function, the use of certain acids is preferred in compounding compositions for topical application to the skin. For compositions of this type, physiologically acceptable acids are employed. Although mineral acids or simple carboxylic acids can be used, it is usually desired that the acid employed have properties other than acidity which are useful in compounding the composition, i.e. that the acid is a functional cosmetic acid.

Numerous functional cosmetic acids have been employed according to the present invention to neutralize amine solutions of heavy metal salts of pyridinethione in the formulation of cosmetic compositions. In these compositions, the acids also function as thickening agents, surface-active agents, or the like.

The following examples, given by way of illustration of the invention, show typical cosmetic compositions suitable for topical application to the hair and scalp. The compositions have been formulated with a variety of functional cosmetic acids, as noted in detail in the examples.

EXAMPLE 1 A one-percent solution of zinc pyridinethione in diglycol amine was prepared. One part of the resulting solution was diluted with nine parts of ethyl alcohol to give a 0.1 percent solution of the salt. Seven parts of the resulting solution were then combined with 5-15 parts of glycerine and 15-35 parts of propylene glycol functioning as hair grooming agents. The composition was brought to a pH of 9 with an aqueous or ethanolic solution of an acid, and brought to 100 parts by weight with additional water or alcohol. Perfume was added as desired.

The resulting clear composition contains the so-lubilized zinc pyridinethione in a concentration of 700 parts per million, or 0.07 percent.

In addition to mineral acids, the following physiologically acceptable and/ or functional cosmetic acids can be employed: sebacic acid; oleic acid; isostearic acid; lauroyl amino diacetic acid; phosphated oleyl alcohol; an ethoxylated lauryl alcohol ester of phosphoric acid; oleyl sarcosine; various hydrolyzed copolymers of methyl vinyl ether and maleic anhydride of differing molecular weight and marketed under the tradename Gantrez; carboxylated copolymers of polyvinyl acetate; an oleic acid polypeptide; stearyland undecenylderivatives of imidazoline of the following structure:

/CE2 N CH and N CHz CHQOOOH For example, by combining 20 parts of a three percent aqueous solution of a carboxy vinyl polymer (Carbopol) with 15 parts of glycerine, 35 parts of propylene glycol, seven parts of a 1 percent solution of zinc pyridinethione in diglycol amine, small quantities of perfume and thickening agent, and bringing the mixture to 100 parts with 95 percent ethanol, a clear hair gel composition is formed in which the functional acid serves both to neutralize the diglycol amine and as a gel forming agent.

With certain of the acids, the compositions had a slight tendency to form crystals on standing for extended periods of time. This crystal formation can be completely inhibited by reducing the concentration of the pyridinethione salt in the compositions, for example to half the value given or about 350 parts per million.

4 EXAMPLE 2 Clear compositions suitable as a rinse or shampoo were prepared as follows:

In these compositions, foaming action is provided by the foaming additive and by soaps formed between the diglycol amine and the acid component, which may comprise C C saturated or unsaturated fatty acids.

Amine solutions of heavy metal salts of pyridinethione of the kind discussed above will precipitate the heavy metal salt if excessively diluted with water. However, it has been found that such heavy metal salts solubilized with a polyalkylene imine, particularly a poly-(lower alkylene) imine such as polyethylene imine or polypropylene imine, will not precipitate the metal salt even on infinite dilution with water.

Polyethylene and polypropylene imines are complex materials whose formulas are generally shown as -(CH CH NH),, and (CH CH CH NH) respectively. However, the polymers are branched, rather than completely linear, and contain primary and tertiary nitrogens in addition to the secondary nitrogens shown in the formulas. In general, the ratio of primary to secondary to tertiary nitrogens in these polyalkylene imines is approximately 122:1. As is known in the art, the polymers are prepared by the polymerization of ethylene or propylene imine in the presence of a proton donor such as an acid or a quaternizing or alkylating agent. Zinc pyridinethione can be dissolved in polyethylene imine of an approximate molecular weight of 600 to an extent of about 33 percent. With increasing molecular weight, solubility decreases but is still about 10 percent in an imine having a molecular weight of 100,000 (the highest available commercially). Such solutions do not precipitate the original salt upon infinite dilution with water. However, the addition of undue amounts of acid to the solution will cause precipitation of the salt. For example, aqueous solutions of zinc pyridinethione in polyethylene or polypropylene imine are conveniently neutralized with concentrated hydrochloric acid or citric acid to a pH of about 8.5. Decreasing the acidity below this level causes the formation of a haze, and precipitation generally occurs at pH 8.3. Because of the water compatibility of the materials, polyalkylene iminesolubilized salts are widely useful, as in the typical formulations shown below.

EXAMPLE 3 The following clear solution is useful as a disinfectant or antiseptic. The composition is bactericidal for Staph. aureus, Staph. albus, E. coli, Pityrasporum ovali, and Candida albfcans, as has been determined by applying the solution to a tube containing a culture of one of these bacteria and then plating out in agar to determine the extent of regrowth.

With the addition of a perfume, the formulation is a suitable clear medicated hair rinse.

Parts by wt. Zinc pyridinethione 2.0 Polyethylene imine 4.0

Concentrated hydrochloric acid to give a pH of 8.59.0. Water to give parts.

EXAMPLE 4 0.5 part by weight of zinc pyridinethione is combined with 1 part by Weight of polyethylene imine and water is added to give parts. This clear aqueous solution has a pH of about 11 and can be used as an anti-dandruff agent in hair straightening solutions, or in highly alkaline hair coloring solutions. On combination with hydrochloric acid to bring the pH to a value of 8.5-9.0, a composition suitable as a hair rinse is obtained.

For pH control of the alkaline solutions of the invention, other mineral acids or physiologically acceptable organic acids can be used, such as citric, oxalic, tartaric, malic, and maleic, all of which are water soluble. Many of the functional acids mentioned earlier can similarly be used in the formulation of compositions.

EXAMPLE 5 Clear liquid aqueous alcoholic hair dressings may be formulated as tabulated below. Table I shows typical compositions and Table II a preferred material.

TABLE I Parts Polyalkylene glycol (e.g. polypropylene glycol,

ethoxylated glycols, mixed polypropylenepolyethylene glycols) 525 Fatty esters (e.g. isopropyl myristate) 0-4 Vegetable oils (e.g. castor oil) 04 Zinc pyridinethione 0.12.0 Polyethylene imine 1 0.24.0 Water 0-16 Denatured ethanol (95%) 45-95 Hydrochloric acid to pH 8.5 q.s. Perfume oil q.s.

1 Or polypropylene imine, 0.8-16 parts (replacing ethanol). Small quantities of additional grooming agents such as glycerine. propylene glycol, or cellulose other derivatives, or of hair fixative polymers such as polyvinyl pyrrolidone may also be included.

An aqueous alcoholic clear hair setting lotion typically has the following composition:

Parts Hair setting resin 1-6 Plasticizer 0.20.8 Polyethylene imine 0.2-4 Zinc pyridinethione 0.1-2 Ethanol (95%) 0-50 Water 3694 Hydrochloric acid to pH 8.6 q.s.

Perfume oil The resin in the formula may be any one of several known to the art for hai rsetting uses such as polyvinyl pyrrolidone (PVP), PVP-vinyl acetate copolymers, methacrylate resins, or amino-methacrylate resins. The plasticizers are also known in the art and may suitably include silicones, fatty esters, fatty alcohols, fatty amines, lanolin derivatives, aromatic esters, and proteinaceous materials.

The compositions shown in Examples 16 are clear, and such clear compositions are only attainable using the solubilized pyridinethione heavy metal salts of the invention. However, the same solubilized salts, in water, can be used to prepare oiland-water emulsions useful for cosmetic or dermatologic purposes. In the emulsions, the salts are present in dissolved solubilized form-and not suspended-principally in the aqueous phase.

What is claimed is:

1. A solution of a fungicidally and bactericidally effective amount of a heavy metal salt of l-hydroxy-Z- pyridinethione dissolved in a member selected from the group consisting of dodecyl amine and diglycol amine.

2. A solution as in claim 1 wherein said salt is dissolved in diglycol amine.

3. A mixture of (1) a fungicidally and bactericidally effective amount of a heavy metal salt of 1-hydr0xy-2- pyridinethione dissolved in a member selected from the group consisting of dodecyl amine and diglycol amine and (2) a quantity of a physiologically acceptable acid imparting a pH between about 7.5 and about 9.5 to said mixture.

4. A mixture as in claim 3 wherein said salt is dissolved in diglycol amine.

5. The method of solubilizing a fungicidally and bactericidally effective amount of a heavy metal salt of 1- hydroxy-2-pyridinethione in a member selected from the group consisting of dodecyl amine and diglycol amine, which method comprises mixing the salt and the amine and then bringing the mixture to a pH between about 7.5 and about 9.5 by the addition thereto of a physiologically acceptable acid.

6. The method as in claim 5 wherein said salt is mixed with diglycol amine.

References Cited UNITED STATES PATENTS 2,809,971 10/1957 Bernstein et al. 252405 X 3,235,455 2/1966 Judge et al. 424263 X 3,236,733 2/1966 Karstein et al. 424263 X 3,281,366 10/1966 Judge et al. 252106 X 3,412,033 11/1968 Karstein et al. 252-106 X 3,489,686 1/1970 Parran, Jr. 252-106 OTHER REFERENCES Chemical Abstracts, vol. 66 (1967), p. 58807X.

SAM ROSEN, Primary Examiner N. A. DREZIN, Assistant Examiner US. Cl. X.R. 424263 

